The overarching theme of this long-standing project is both a comprehensive and in depth understanding of the biology of arsenic, the most pervasive environmental toxic substance and carcinogen in nature. The Environmental Protection Agency calls arsenic the most prevalent environmental toxin and carcinogen in the United States (http://www.atsdr.cdc.gov/cercla/07list.html). Arsenic causes cardiovascular and peripheral vascular diseases, neurological disorders, diabetes mellitus and various forms of cancer such as skin and bladder cancer. We have described steps in the biogeocycle for inorganic arsenic and identified a parallel biocycle for organoarsenicals. We hypothesize that members of microbial communities synthesize methylarsenite (MAs(III)) by methylation of inorganic arsenite (As(III)) and use this extremely toxic organoarsenical as an antibiotic against other bacteria. Man has created even more toxic synthetic organoarsenicals for use as herbicides and antimicrobial growth promoters. In response to environmental pressures, bacteria evolved resistance mechanisms against both biological and synthetic toxic organoarsenicals. Our overall goal is to characterize the pathway of arsenic methylation and detoxification at the functional, mechanistic and structural levels. We propose three specific aims: 1) synthesis of MAs(III), 2) breakdown of MAs(III) and 3) efflux of MAs(III). We unify these physiological functions in a new and novel hypothesis on the evolution of antibiotics.